Substituted 1, 3-di-amino-2-propanols



. ing general scheme:

Patented 27,1931

UNITED STATES PATENTLOFFICE OTTO EISLEB, OF HOFHEII, Gm, ASS HD10 3, BY MESNE ASSIGNMENTS, TO WIN- THROP CHEMICAL'COHPAN Y, NEW YORK, N. Y., A CORPORATION OF NEW YORK sunsrrrurnn ns-m-n rmo-z-rnormons No Drawing. Application filed July 28,1927, Serial No. 209,177, andin Germany August 3, 1926 My present invention relates to new asymmetrically substituted 1.3 di-amino-2 propanols and to a process of preparing the same.

There have already for some time been known 1.3-diamino-2-propanols Qsymmetncally substituted at the two nitrogen atoms obtainable by the reaction of dichlorhydrin or epichlorhydrin with a base and which, owmg to the easy way in which they can be prepared, are utilizedas parent material 1n the manufacture of therapeutically valuable substances. However, for the preparation of asymmetrically substituted 1.3-di-amino-2- propanols no synthesis has as yet been known.

Now I have found that the alpha-tertiary amino epihydrins, some ofwhich have onlyvaguely been in literature and have not at all been studied as regards their reactions, can be easily obtained from epichlorh 2o drin andsecondary bases under suitable wor ing conditions and, when subjected to reaction with a nitrogen base such as ammonia, a primary or secondary amine, yield 1.3-diamino-2-pr0panols unequally substituted at both nitrogen atoms. The reaction takes place in three stages according to-the followcmcl heterocyclic nitrogen containing nucleus,

, In this manner compoun s can be obtained one amino group of which is a tertiary one, the other amino oup being either a tertiary one which is di erent from theformer, ora secondary. or primary one. The asymmetrito- C. by

and R, and R stand for gydrogen or'alkyL' point under 760 mm.

cally substituted l.3-di-amino-2propanols are intended to be used asintermediate prodnets in the manufacture of therapeutic agents. They can be represented by the general formula:

wherein N is a nitrogen of a tertiary amine; R and R standing for alkyl, aryl or carbon atoms, belonging to a heterocyclic nitrogen containing nucleus, and X represents a primary, secondary or tertiary amino-group, be-

ing linked to the CH group by means of its mg in a suitable manner to such 'an extent that the temperature of the mixture remains between 28 C; and 30 C. When,

, after about 2 hours, the heat evolved dur-. ingthe reaction has abated, the mixture is kept for another 2 to 3 hours at 28 C. -a suitable external heating.

The product of the reaction is then shaken 'out with 500palrts by volume of a 20% solution of potassium carbonateaand after the r,

b latter'h'as beenseparated, the product is again well shaken with 600 parts by'volume of caus- ;ti'c soda'solu'tion' of 40 B. for -60 minutes during which operation sodium chloride separates with slight selfheating. The very mobile layer consisting of crude diethyl-amino-epihydrinis separated ;from the salt solution, well shaken. for a. short time with a caustic potash solutionof strength and after isolation distilled. in .a vacuum. Theof diethylamine are produ'ct,-whi'ch .runs over at 40 C. to 50 C.

under 8 mm. pressure is collected, its boilin J pressure being to 159 C. It is a colorlessirery mobile liquid of an intensely" has1c smell which is mis cible with water and can be re-separated from its aqueous solution by means of a caustic soda solution. ()n storing the substance for a considerable time, it gradually undergoes Nm.onaomonyon moimn boils at 223 C. under 760 mm. pressure and is a colorless oil of a slightly basic smell, miscible with water with selfheating (formation of a hydrate) and also miscible in ether; it can be salted out from an aqueous solution by means of potassium carbonate.

Preparation of J-cthyiamz'no-5-diethylamino-2-pr0panol.130 parts of diethylamino-epihydrin are heated in a bomb for one hour to 120 C. to 130 C. with 500 parts of an alcoholic solution of ethylaI-nine of about 47% strength. After cooling, the mass is subjected to fractional distillation first under ordinary and then under reduced pressure.

Thus, a fractional distillate is obtained which distils over between 100 C. to 120 C. under 6 mm. pressure. Under normal pressure, the product boils at between 230 C..to 232 C. It is a colorless oil of a weak smell and has the-probable formula:

3. Preparation of J-aminofi-pipefldino-Q- propa'nol and piperidinoegfihydm'n.lfnto 100 parts of epichlorhydrin are introduced drop by drop 98 parts of piperidin-e at a temperature of 28 C. to 30 C. while stirring and cooling in a suitable manner. The heat evolved during the reaction is very considerable. After one to one and a half hours the heat has entirely abated. The mixture is allowed to stand for a further three hours and then first shaken out with a 20% solution of potassium carbonate and then again with 150 parts by volume of a caustic soda solution of 40 B. for one hour. The thin liquid oil layer is separated, dried over potassium hydroxide and distilled in a vacuum.

kept at this temperature for-30 minutes. 'By' fractional distillation the 1-amino-3-p1- peridino-2-propanol of the probable formula onion NHz.OHz.CH(OH).OHz.N on

onion is obtained as a colorless liquid slightly smelling like alkamine; it distils over at 148 to 150 C. under a,pressure of 29 mm. This product soon solidifies entirely into a mass composed of radiated crystals.

j Pa'epa'rat-ion of 1-amin0-3-(pheny Z- mating Lamina)-2-pr0panol and alplta phes nylmethylamno-epihydrin.318 parts of monomethylaniline, 300 parts of methyl alcohol and 300 parts of epichlorhydrin are gently heated together in a flask on the water-bath and under reflux cooling. The mass soon begins to boil which continues for about one hour after stopping the supply of heat. The mixture is then boiled for another 6 hours in the reflux apparatus, at the end of which time all epichlorhydrin has been transformed as is shown by the fact that a test sample givesa clear solution in diluted sulfuric acid. After the ethyl alcohol has been distilled off in a vacuum at 60 (L, the residue is mixed and stirred for 2 hours with {150 parts by volume of caustic soda solution of 40 Be, the oilseparated, once well shaken with acaustic potash solution of 50% strength, again separated and distilled in a vacuum; the product distils over at 132 C. to135 C. under 8 mm. pressure, or at 160 C. to 162 C. under 30 mm. pressure. The product is an oil, smelling, but very slightly, like dimethylaniline, being almost colorless, dissolving very sparingly in water ing the probable formula:

omononm H 135 parts of the phenylmethylamino-epihydrin so obtained are heated in a bomb to 100 C. with a solution of 250 parts of am- 'monia in 1500 parts of methyl alcohol and the mixture is kept at this temperature for '2 l10ll!S.' The new base separated by the ing at 71 C. It has the probable formula I claim: I 1. As new products the compounds of the general formula: It distils over at 72 C. to 77 C. under 8 n mm. pressure. 100 parts of piperidinoepihywherein R represents hydrogen or alkyl.

As a new product, the compound of the general formula:

CIHI

and hav being a colorless oil boiling under a'pressure of 760 mm, at 223 0., havin a slightly basic smell and being miscible water. 3. The proces which comprises causing a secondaryibase to react with epichlorhydrin' in 'monomolecular proportions treating the intermediate product thus obtained with caustic alkali, and then treating the resulting compound with a nitrogen base containing at least one hydrogen atom linked to the nitro-.

4. The process which comprises causing diethylamine to react with epichlorhydrin in monomolecularproportions, treatin the in- II termediate product thus obtained wit caustic. alkali, and then treating the resulting compound with a nitrogen base-containm at least one hydrogen atom linked to the nitrogen. u

5. The process which comprises causing a secondary base to react with epichlorhydrin in monomolecular proportions, treating the intermediate product thus obtained with causstic alkali and then treating the resulting compound with ammonia.

6. The process which comprises fcausing diethylamine to react with epichlorhydrin in monomolecular proportions, treatin the'intermediate product thus obtained wit caustic 3 alkali and then treating the resulting compound with ammonia. I

7 The process which comprises causing a secondary to react'with epichlorhydrin in monomolecular proportions, treating the intermediate product thus obtained with cans} tic alkali, and then treating the resulting compound with methyl-alcoholic ammonia:

8.--The rocess which comprises causing diethylamme to react with epichlorhydrin in 40 monomolecularproportions, treatin the intermediate product thus obtained with caustic alka1i,..and then treating the resulting compound with'methyl-alcoholic ammonia. I f -9. As new products the compounds of the general formula:

in R and R, standing n V v n;

tw s m ms.

' wherein N is a nitrogen of a tertiary amine;

or aIkyLaryIoncaI-bon belonging to a heterocyclic nitrtgzn eontaininfiypucleug and R, represents hy gen or lntestimonywhereofflafixmfi' 'ature,

f's'iina. 

